Solubilization of poorly water-soluble drugs is essentially required to deliver the drugs into the body by oral or parenteral administration. Drug delivery systems are designed to maximize efficacy and effects of drugs and to minimize side effects of drugs. In particular, efficacy of poorly water-soluble drugs that are not easily dissolved in water can be enhanced remarkably by solubilizing by drug delivery systems. Most drugs, after administration, must have a constant plasma concentration in order to provide desired pharmacological effects. In particular, drugs with short half-life should be administered frequently to achieve effective plasma concentration, and be slowly released from the preparation to maintain sustained pharmacological effects. To do so, micelles formed by polymer used for solublizing poorly water-soluble drugs should be more stable, for which the critical micelle concentration (CMC) should be low, and the affinity between poorly water-soluble drugs having high hydrophobicity and hydrophobic block of copolymer should be increased.
The unit size of droplet of micelles formed by surfactant can be controlled to several nm to several tens μm, and so the micelles are in the form finely dispersed in solutions since poorly water-soluble drugs solution are contained in the droplet. Thus, the method to form micelles to solublize poorly water-soluble is regarded as most preferable, and so among the solubilization methods using micelles, use of surfactant is one of key technologies.
Recently, as a method for solubilizing and delivering poorly water-soluble drugs, there have been many studies for methods delivering poorly water-soluble drugs by entrapping the drugs into the core of micelles or nanoparticles formed of amphiphilic block copolymer consisted of hydrophilic polymer and hydrophobic polymer.
For example, U.S. Pat. No. 5,543,158 discloses a dosage form that drug is entrapped into nanoparticle formed of amphiphilic block copolymer consisted of a hydrophilic polyethylene glycol block and a hydrophobic copolymer of polylactide and polyglycolide block. Also, U.S. Pat. No. 6,322,805 discloses a technology to solubilize poorly water-soluble drugs by using biodegradable polymers comprised of monomethoxypolyethylene glycol and polylactide as an amphiphilic diblock copolymer, wherein poorly water-soluble drugs is physically contained into core of micelles and solubilized in aqueous solution without chemical combination.
As shown above, prior poorly water-soluble drugs required hydrophilic polymer such as polyethyleneglycol, etc. to have core-shell structure in addition to biodegradable hydrophobic polymer like polyesters. Here, the hydrophilic polymer such as polyethyleneglycol is biocompatible element, but is not completely degraded in human body, while the polyester based hydrophobic polymer can be degraded in human body. Thus, there have been attempts to develop a drug delivery agent of core-shell structure with only bio-degradable polyesters hydrophobic polymer without hydrophilic polymer.
In particular, polylactic acid has very good biocompatibility, and is hydrolyzed into lactic acid harmless to human body. Thus, it has been developed in the form of microsphere, implant agent, etc., by using a characteristic that polymer having molecular weight of 2,000 dalton or more is not soluble in aqueous solution. However, the hydrophobic polymer could not form micelles to solubize poorly water-soluble drugs, and so could not be developed as drug delivery agent for solublizing poorly water-soluble drugs, only with polylactic acid polymer.
Thus, the present inventors have prepared linear polylactic acid derivatives wherein the balance between hydrophilic group and hydrophobic group is adjusted by binding carboxyl group to the terminal of polylactic acid to form polymeric micelles in aqueous solution, and filed the invention as Korean Patent Application No. 2001-64164. However, the polylactic acid derivatives have linear structure that only one molecule of carboxyl group is bound to the terminal, and so the molecular weight of the polylactic acid derivatives capable of forming polymeric micelles in aqueous solution was limited to the range of 2,000 Dalton and less. Also, micelles could not be formed in the higher molecular weight since the derivatives could not be dissolved in aqueous solution. In short, the above polylactic acid derivatives have relatively low molecular weight and cannot entrap the drug in the micelle for a long time due to the poor stability of formed micelles.
Also, Y. Li, et al. discloses that in case of using amphiphilic polymer formed by branched polymer or multi-armed polymer as drug delivery agent, the structural stability of drug delivery agent is enhanced since the polymer has slower biodegradation rate than linear polymer [Polymer, 39, pp. 4421-7(1998)]. This article also used branched polyethyleneglycol as an initiator, and synthesized the branched diblock copolymer by linking mono-polymer or co-polymer such as polylactic acid, polyglycolide and polycaprolactone etc. to each branch. Microparticles or hydrogel containing drug was prepared from these polymers so that drug is released according to the biodegradation rate of polymers. Further, in the U.S. Patent Application Publication No. 2002-0156047, polylactic acid was synthesized and linked with hydrophilic polyethyleneglycol to each of its branches to use as drug delivery agent. This application discloses that the synthesized branched diblock copolymer can effectively entrap hydrophobic drug since the hydrophobic polylactic acid is placed in core region at the middle. However, the drug delivery agent in the above references has a problem that the used hydrophilic polymer is not fully degraded in the human body since the drug delivery agent uses polyethyleneglycol as hydrophilic block of amphiphilic block copolymer.
On the other hand, there is a report to have synthesized branched polymer consisted of only biodegradable polyesters polymer without using polyethyleneglycol. For example, a report shows that pentaerythritol is used as an initiator to synthesize 4-arm branched polycaprolactone, to link maleic anhydride to the 4 hydroxy terminal groups, and to bridge-bind by using UV [M. Lang, et al., J. Appl. Polymer Sci., 86, 2296 (2002)]. Also, there is a report that polyol is used as an initiator to synthesize a branched polylactide, to link methacryloyl chloride to each hydroxy terminal group to synthesize macromer, and then to synthesize porous scaffold by reacting dibenzoyl peroxide [M. Schnabelrauch, Biomaterial Engineering, 19, 295(2002)]. However, these branched polymers have disadvantages that they cannot be used as drug delivery agent since they cannot be solubilzed in aqueous solution due to imbalance between hydrophilic part and hydrophobic part, and that they are not biodegradable in human body since they are cross-linked to improve the mechanical property as medical device.